Renin-angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis

Abstract

Background: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated with an increased susceptibility to COVID-19 in patients with hypertension.

Methods: In this international, open science, cohort analysis, we used electronic health records from Spain (Information Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes: COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons, with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.

Findings: Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84-1·14) or combination use exposure (1·01, 0·90-1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or THZ monotherapy (HR 0·91, 95% CI 0·68-1·21; with heterogeneity of >40%) or combination use (0·95, 0·83-1·07). Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with combination use (HR 0·88, 95% CI 0·79-0·99) and non-significant for monotherapy (0·85, 0·69-1·05). We observed no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis across all comparisons.

Interpretation: No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to decrease their risk of COVID-19.

Funding: Wellcome Trust, UK National Institute for Health Research, US National Institutes of Health, US Department of Veterans Affairs, Janssen Research & Development, IQVIA, South Korean Ministry of Health and Welfare Republic, Australian National Health and Medical Research Council, and European Health Data and Evidence Network.

Figure 1

ICARIUS susceptibility study design We highlight eligibility criteria, exposure definitions, adjustment strategies, index date specification (day 0; horizontal black arrow), and outcome definitions and time at risk. Exposure involves prescriptions to drugs with RxNorm ingredients that map to the first-line antihypertensive drug classes: ACEIs, ARBs, CCBs, and THZs. ACEI=angiotensin-converting enzyme inhibitor. ARB=angiotensin receptor blocker. CCB=calcium channel blocker. CUIMC=Columbia University Irving Medical Center data warehouse. ICARIUS=International Covid-19 ACE Receptor Inhibition Utilization and Safety. SIDIAP=Information Systems for Research in Primary Care. THZ=thiazide or thiazide-like diuretic. VA-OMOP=US Department of Veterans Affairs Observational Medical Outcomes Partnership. *For monotherapy analysis only; other antihypertensive therapy included rate-limiting CCBs, diuretics, and β blockers. †Day 0 is the most recent observed prescription for target or drug comparator between Nov 1, 2019, and Jan 31, 2020.

Figure 2

Cohort balance diagnostics comparing ACEI or ARB and CCB or THZ monotherapy prevalent use for the risk of COVID-19 diagnosis We plotted the absolute standardised difference in population proportions of all available patient characteristics (6571 in SIDIAP, 11 183 in VA-OMOP, and 18 291 in CUIMC) before and after propensity score stratification or matching across data sources. Using stratification, CUIMC fails study diagnostics for this comparison as the absolute standardised mean difference is not consistently less than 0·1. Dashed lines indicate no before and after adjustment. ACEI=angiotensin-converting enzyme inhibitor. ARB=angiotensin receptor blocker. CCB=calcium channel blocker. CUIMC=Columbia University Irving Medical Center data warehouse. SIDIAP=Information Systems for Research in Primary Care. THZ=thiazide or thiazide-like diuretic. VA-OMOP=US Department of Veterans Affairs Observational Medical Outcomes Partnership.

Figure 3

Calibrated HRs for COVID-19-related outcomes for ACEI, ARB, CCB, and THZ prevalent use across data sources Outcomes are COVID-19 diagnosis, hospital admission with COVID-19, hospital admission with pneumonia, and hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We plot calibrated HRs and their 95% CIs (indicated by error bars) labelled by propensity score adjustment method. Greyed out data source entries do not pass study diagnostics and greyed out meta-analysis entries return a heterogeneity (I²) value of more than 40%. ACEI=angiotensin-converting enzyme inhibitor. ARB=angiotensin receptor blocker. CCB=calcium channel blocker. CUIMC=Columbia University Irving Medical Center data warehouse. HR=hazard ratio. SIDIAP=Information Systems for Research in Primary Care. THZ=thiazide or thiazide-like diuretic. VA-OMOP=US Department of Veterans Affairs Observational Medical Outcomes Partnership.